Abstract
Endotoxin tolerance aims at opposing hyperinflammatory responses to lipopolysaccharide (LPS) exposure. The aryl hydrocarbon receptor (AhR) participates in protection against LPS-mediated tissue damage, as it plays a necessary role in restraining the proinflammatory action of IL-1β and TNF-α while fostering the expression of protective TGF-β. TGF-β, in turn, promotes durable expression of the immune regulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 degrades L-tryptophan to L-kynurenine—an activating ligand for AhR—thus establishing a feed-forward loop. In this study, we further demonstrate that L-kynurenine also promotes the dissociation of the Src kinase–AhR cytosolic complex, leading to the activation of both genomic and non-genomic events in conventional dendritic cells (cDCs) primed with LPS. Specifically, the Src kinase, by phosphorylating the downstream target IDO1, triggers IDO1’s signaling ability, which results in enhanced production of TGF-β, an event key to establishing full endotoxin tolerance. We demonstrated that exogenous L-kynurenine can substitute for the effects of continued or repeated LPS exposure and that the AhR–Src–IDO1 axis represents a critical step for the transition from endotoxin susceptibility to tolerance. Moreover, much like fully endotoxin-tolerant dendritic cells (DCs) (i.e., treated twice with LPS in vitro), DCs—treated once with LPS in vitro and then with kynurenine—confer resistance on naïve recipients to an otherwise lethal LPS challenge. This may have clinical implications under conditions in which pharmacologically induced onset of endotoxin tolerance is a therapeutically desirable event.
Highlights
A first exposure to lipopolysaccharide (LPS) makes mice resistant to shock caused by a subsequent LPS injection, an occurrence known as LPS or endotoxin tolerance
We found that L-kynurenine can replace a second exposure to LPS in triggering genomic and non-genomic, aryl hydrocarbon receptor (AhR)-dependent effects capable of rendering conventional dendritic cells (DCs) suitable for transferring endotoxin tolerance onto naïve recipients
Treatment of conventional dendritic cells (cDCs) with Lkynurenine in the absence of prior LPS did not affect Ido1 expression (Figure 1A), implying that early TLR4-dependent events are necessary for initiating the loop whereby L-kynurenine will later reinforce AhR-dependent Ido1 transcription
Summary
A first exposure to lipopolysaccharide (LPS) makes mice resistant to shock caused by a subsequent LPS injection, an occurrence known as LPS or endotoxin tolerance. In infection resistance and disease tolerance to microbial insult, the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) adaptively balances aggressive immune responses (“resistance”) with the host’s ability to withstand the negative effects of infection, namely, L-Kynurenine and IDO1 Control Hyperinflammation immunopathology or damage due to pathogen metabolism and virulence factors (“tolerance”) [3, 4]. The main interest is shifting from the role of AhR in the hepatic metabolism—and inactivation—of potentially toxic xenobiotics toward the nature of its physiological ligands as well as its mode of action in response to functionally distinct molecules, which are remarkably different in nature as to their endogenous source and chemical structure. Tryptophan metabolites, including L-kynurenine, act as activating molecules for the receptor [3, 5]
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